The ulcerative colitis is a chronic inflammatory form of the colon mucosa; in particular, the inflammatory reaction concerns the large intestine, i.e. the colon with localization in the terminal tract, the rectum and the sigmoid flexure, while the ileum is only seldom involved. In the most serious cases the inflammation can spread to the submucosa.
Crohn's disease or granulomatous colitis is a manifestation of inflammatory type, which usually affects the small intestine, the jejunum and the whole colon, including also the rectum. This inflammatory reaction differs from the ulcerative colitis as, normally, involves deeper layers of the mucosa.
The differential diagnosis between ulcerative colitis and Crohn's disease is often problematic, so that the international medical literature frequently uses the common term “Inflammatory Bowel Disease” (IBD) to jointly indicate these pathologies.
The therapeutic approach in the various forms of the IBD includes the use of corticosteroids such as prednisone, prednisolone or hydrocortisone, above all in the acute attacks, together with the administration of liquids, plasma and electrolytes.
For the treatment of the forms from slight-moderate to chronic IBD, in the past, sulfasalazine was commonly used, whose mechanism of action is not completely well-known: sulfasalazine, orally administered, reaches unmodified the colon, where it is transformed by the resident bacteria into sulfapyridine and mesalazine.
Today mesalazine is commonly accepted as the pharmacologically active moiety of sulfasalazine, while sulfapyridine would have just the role of carrier, bringing the active moiety at the site of action.
Sulfapyridine is not free of toxicity and the intolerance toward such molecule is frequent; therefore, in the last years, much interest has been addressed to the utilization of mesalazine as active ingredient for the treatment of the forms from slight-moderate to chronic IBD.
The oral administration of mesalazine is made nevertheless problematic by the fact that such drug is almost completely absorbed in the small intestine and, therefore, just a small amount reaches the colon to carry on the therapeutic action. With the aim of overcoming such difficulty, during the past, formulations of mesalazine with particular coatings were developed, exhibiting the characteristic to release the active ingredient only in the desired area, also to avoid systemic side effects. These pharmaceutical compositions are retard, or slow release, forms, suitable to prevent or delay the absorption of mesalazine in the proximal tract to obtain therapeutic concentrations in the ileum and colon.
The most wide-spread formulations available on the pharmaceutical market are pH-dependent, time-dependent or bacterium-dependent.
Document EP 0 040 590 (Aktiebolaget Hassle) describes oral pharmaceutical preparations able to release a drug, for example mesalazine, selectively in the colon, starting from pH 5.5.
This is obtained through a coating of the active ingredient with a mixture of an acrylic anionic polymer soluble just at pH 5.5, such as, for example, Eudragit L, in quantities ranging from 10 to 85%, and an acrylic polymer substituted by quaternary ammonium, insoluble in water, like, for example, Eudragit RS or RL, in quantities ranging from 15 to 90%. In these formulations the selective release of the active ingredient in the intestine is obtained through the utilization of a polymer having a pH-dependent solubility. The blending with one or more polymers having a pH-independent solubility prevents the active ingredient from being released too rapidly, once reached the pH of solubilization.
Document EP 0 097 651 (J. B. Tillott Ltd.) regards a solid oral dosage form, for example a capsule or a tablet, containing a pharmacologically active agent, for example mesalazine, for the treatment of colon pathologies. Such solid form is coated with an anionic polymer, insoluble up to pH 7.
Document EP 0 572 486 (J. B. Tillott Ltd.) claims an oral dosage form suitable to dose <selectively a drug in the intestine, including a plurality of granules of active ingredient contained in a capsule. Both the granules and the capsule are coated with equal or different materials, soluble in the intestine, in the ileum or colon, depending on the coating, and this allows a more gradual release of mesalazine in the colon, avoiding, in this way, possible local irritations due to a too rapid release. Preferably, the coating of the pharmaceutical forms is composed by polymers that start dissolving at pH ≧7.
Document IT 1246382 (Eurand International S.p.A.) includes several controlled release oral formulations. In particular, it describes compositions coated with a polymer, for example, Eudragit S, which starts slowly dissolving at pH 6.2, applied onto a second polymeric layer, for example ethylcellulose, to provide a release of the active ingredient at pH 7.2. To obtain the desired effect the two membranes have to be applied in a sequence, otherwise, coating the active ingredient with a mixture of the two components, the dissolution of the solid form in the colon turns out to be too rapid.
Document EP 0 629 398 (Tanabe Seiyaku Co. Ltd.) refers to pharmaceutical preparations able to provide a controlled release of the active ingredient in the desired zone of the intestinal tract (duodenum, small intestine, colon, rectum), and anyway at a pH ≧5, through a proper choice of the coating, and checking, furthermore, the dissolution speed of the drug itself. Among the many coatings indicated as useful, Eudragit L and Eudragit S are mentioned.
All the above described formulations have in common the characteristic to start the dissolution of the coating layer at a pH >5–6, but the real release of the active ingredient occurs either slowly at a pH higher than 6–6.5, or in a rapid way at a pH higher than 7.
The above mentioned patents are based on the use of a polymer having a solubility depending on the pH: when the formulation reaches intestinal regions having pH values in which the polymer is soluble, the liberation of mesalazine begins, which can be very rapid or delayed in case the formulation contains also polymers with a pH-independent solubility. It is nevertheless very difficult with these formulations to obtain the homogeneous distribution of the active ingredient in the area affected by the inflammatory reaction.
It is therefore necessary to develop new pharmaceutical formulations suitable to assure a uniform release of mesalazine in all the intestinal regions target of the therapeutic action.